Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

Sangmi Ock, Jihyun Ahn, Seok Hong Lee, Hongryeol Park, Jang Won Son, Jae Gyun Oh, Dong Kwon Yang, Wang Soo Lee, Ho Shik Kim, Jaerang Rho, Goo Taeg Oh, Evan Dale Abel, Woo Jin Park, Jeong Ki Min, Jaetaek Kim

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Aims: Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression. Methods and results: A marked increase in RANKL expression occurred as early as 6h following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 17 days. An increase in tumour necrosis factor-α (TNF-α), interleukin (IL)-1α, and IL-1β was observed in the hypertrophied hearts only at 3 or 17 days after TAC. Treatment with losartan significantly attenuated TAC-induced cardiac hypertrophy, in parallel with decreased expression of RANKL, TNF-α, IL-1α, and IL-1β. Furthermore, injection of a RANKL-neutralizing monoclonal antibody attenuated RANKL-induced cytokine expression. RANKL stimulated expression of TNF-α, IL-1α, and IL-1β in neonatal rat cardiomyocytes via activation of NF-κB. RANKL-induced NF-κB activation and expression of these cytokines were both attenuated when RANK, receptor for RANKL, or TRAF2 or TRAF6, adaptors for RANK, was silenced by siRNA. Furthermore, inhibitors of phospholipase C (PLC), protein kinase C (PKC), and inhibitor of κB kinase also significantly inhibited RANKL-induced cellular activities, but inhibitors of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase were without effect. Conclusion: Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANKTRAF2/TRAF6PLCPKCNF-κB-mediated autocrine mechanism. Published on behalf of the European Society of Cardiology. All rights reserved.

Original languageEnglish
Pages (from-to)105-114
Number of pages10
JournalCardiovascular Research
Issue number1
StatePublished - 1 Apr 2012

Bibliographical note

Funding Information:
This work was supported by a grant from the Korea Healthcare technology R&D Project (A101749), Ministry of Health & Welfare, Republic of Korea, to W.J.P and J.K.


  • Cardiomyocytes
  • NF-κB
  • Proinflammatory cytokine


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